The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
The mode of action of UV radiation in the skin is a major challenge in photoimmunology. Studies in animals and humans have established that UV exposure yields both local and systemic immunological unresponsiveness and tolerance (Schwarz 1999). The ultraviolet B (UVB) wavelengths (280-315 nm) have been found to account for most of the immunosuppressive activity of UV irradiation. The agents responsible for direct absorption of the UVB photons in epidermis include urocanic acid (UCA) and DNA. Endogenous trans-UCA, synthesized by enzymatic deamination of histidine in the stratum corneum of the skin, is directly photoisomerized to cis-UCA upon exposure to UVB radiation. It has been well demonstrated, both in vitro and in vivo, that photoisomerization of UCA plays a role in UVB-induced immunosuppression. For instance, the systemic suppression induced by UVB irradiation can be largely reversed by anti-cis-UCA antibodies in mice (Moodycliffe 1996). Furthermore, in several animal models, local or systemic administration of cis-UCA produces immunosuppressive effects similar to UVB treatment (Gruner, 1992; el-Ghorr, 1997; Garssen, 1999, Wille 1999). Some experiments have shown that UCA is capable of modulating certain functions in isolated cells of the immune system in vitro, such as antigen presentation (Beissert 1997, Holá{circumflex over (n)} 1998), NK-cell cytotoxicity (Gilmour 1993, Uksila 1994), cytokine production by spleen cells (Holá{circumflex over (n)} 1998), degranulation of mast cells (Wille 1999) and activation of neutrophils (Kivistö 1996).
Neither in vivo nor in vitro studies have yet clarified which immune cells actually interact with UCA after UVB exposure and by which mechanism this molecule affects the function of the target cells at the molecular level. One would expect that UCA is a soluble mediator binding to cell surface receptors and initiating a signaling cascade. However, little is known about the putative receptor(s) of UCA. It may share some common properties with the histaminergic system, because histamine H1 and H2 receptor antagonists partially block cis-UCA induced immunosuppression (Hart 1997). On the other hand, it has been shown that cis-UCA does not directly bind to histamine receptors (Laihia, 1998). Recently, displacement studies indicated that UCA may act on GABA receptors, but no direct evidence of UCA binding to this receptor was demonstrated either (Laihia, 1998; Uusi-Oukari, 2000).